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Locus Heterogeneity Definition Diagram when two or more DNA variations in distinct genetic loci are independently associated with the same trait Allelic Variant i Of Locus A Allelic Variant ii Of Locus B Disease X Trait Heterogeneity Gene-Gene Interaction when a trait, or disease, has been defined with insufficient specificity such that it is actually two or more distinct underlying traits when two or more DNA variations interact either directly (DNA-DNA or DNA-mRNA interactions), to change transcription or translation levels, or indirectly by way of their protein products, to alter disease risk separate from their independent effects Trait I Trait II Allelic Variant i Of Locus A Allelic Variant ii Of Locus B Disease X No Disease Disease X Example One Retinitis Pigmentosa (RP, OMIM# 268000) - genetic variations in at least fifteen genes have been associated with RP under an autosomal recessive model. Still more have been associated with RP under autosomal dominant and X-linked disease models2 (http://www.sph.uth.tmc.edu/RetNet) Autosomal Dominant Cerebellar Ataxia (ADCA, OMIM# 164500) - originally described as a single disease, three different clinical subtypes have been defined based on variable associated symptoms,6,7 and different genetic loci have been associated with the different subtypes8 Hirschsprung Disease (OMIM# 142623) variants in the RET (OMIM# 164761) and EDNRB (OMIM# 131244) genes have been shown to interact synergistically such that they increase disease risk far beyond the combined risk of the independent variants12 Example Two Tuberous Sclerosis (TS, OMIM# 191100) - out of families informative for linkage analysis, half have mutations in the TSC1 gene (located at 9q34) and the other half have mutations in the TSC2 gene (located at 16p13)3,4,5 Autism (OMIM# 209850) - parents and other relatives of autistic individuals often exhibit one or two, but not all three, of the requisite autistic symptomatologies, suggesting autism may be the co-occurrence of three distinct traits.9 Using subset analysis, some success has been achieved identifying genes associated with one of the three symptomatologies but not as strongly with the broader autistic phenotype10,11 Creutzfeldt-Jakob Disease (CJD, OMIM# 123400) and Fatal Familial Insomnia (OMIM# 176640.0010) - the Met129Val polymorphism and Asp178Asn mutation in the PRNP gene (OMIM# 176640) interact, such that when the val129 polymorphism is on the same chromosome as the asn178, the phenotype is fatal familial insomnia 13-19